Improved hydrogenation process



United States Patent ice IMBRQVED GE AIIQN PROGESS. Joseph Levy UniQ and George A. nemqtsgy, Ngwark N. J., assignors to NoPco Chemical Company, Haub son, N. J., a corporation f NeWJerSy N0 Drawingpp eatiqmAu ust- 5.5.0. SerialNo. 1781,5539.

18 Claims. (Cl. 160-2931) This invention relates toanirnproved; hydrogenation Pr c s and, m e p t r -relatss. o an imp ove siye Raney-nickel catalystin such reductions f {th use f. a ete ap n a a y a en c nihea eidsdi ever, uch ed t ns, nss ss ta, have; been out at relatively high temperatures, e. g. 125 C., and under high pressures, e. g. 140 atmospheres. Quite a urally su h ondi on require rather: elaborate equipnent: or; h hydrog n t on r actionv which equipmen of course,is quiteexpensive. Otherprior-art processes employ platinum oxide as a hydrogenation catalyst; however, this catalyst is. quite expensive. and its use considerably increases the cost: of; a. hydrogenation process. as compared to hydrogenation. processes. catalyzed by Raney nickel.

It: is. the object of this invention to. provide. animproved process for the reduction of piperidone compounds topiperidinol compounds.

A further object of this invention is to provide. an improved process for the hydrogenation. of nitrogen substituted piperidone compounds. in the. presence of R aney nickel catalyst.

Other objects of the invention. will in part be. obvious and will in part appear hereinafter.

The above and other objectsofi the. invention are ac- .to completion at room temperature and at relatively low pressures. Thus our novel process is readily carried out inrelatively inexpensive low-pressure hydrogenation equipment. i

In the process of our invention any nitrogen-substituted compound having an alkyl, cycloalkyl, arylalkyl or aryl group substitutedon the nitrogen atom can be reduced to the corresponding .piperidinol eornpoun d. Ge po nds of this a ure e N meth l pinelid i ethyl p perid n N-cyc open y pipet d ne; N -q slq tsay piperidoue, N-phenyl piperidone, N-benzyl piperidone, .fit

2,776,293 Patented Jan. 1, 1957 The solvent employed in the process of the invention can be any aromatic hydrocarbon solvent such as toluene, xylene, cumene, benzene, etc., or any saturated aliphatic hydrocarbon solvent such as hexane, heptane, octane, nonan'e, decane, naphtha, methyl cyclohexane, etc. The amount of solvent employed in the process is not critical except that a sulficient quantity of solvent to dissolve the piperidone free base completely must, of course, be employed. The free pipen'done compounds arerelatively stable in these solvents and a good'yield of the desired piper'idinol compound is obtained form reductions in these media. The solvent We prefer to employ in our novel process is toluene.

' Raney nickel catalyst is well-known in the art as a hydrogenation catalyst. Its composition has been fully described in U. S. Patent, No. 1,628,190 of Raney in I; A. Q. S. 54, 411611932) and in thetextbook Organic Synthesis, vol. 21, page 15, p ublishe, d in 19 41 by John Wiley and Sons, I nc., New York. Essentially, this catalyst isnickelin a finely divided, highly active form. It is prepared'byreacting an alloy consisting of about 50% aluminum and 50% nickel with, a solution of sodium or potassium hydroxide until the alkali dissolves the aluminum leaving the nickel'in the .desired state. of subdivision. The catalyst is then washed several times with Water and stored in Water, or some other suitable solvent, until used. For example, after it has been washed with water, it can be washed with alcohol to remove the 'water, then Washed With toluene andthen finally stored in toluene untilit is tobe used.

The outstanding feature of; our invention is the fact that by carrying out the hydrogenation in the presence ofa very large amount of Raney nickel catalyst, we are able to hydrogenate the piperidone compoundto the piperidinol compound rapidly at roomtemperatur e and at relatively low pressure Whereas the prior art hydrogenation procedures have all required the, use of high temperatures and high pressures to hydrogenate the piperidones to the piperidinols in the presenceof Raney nickel catalyst. In the preferred embodiment of our invention, we carry out the hydrogenation at a hydrogen pressure of from. about, 2 to about 5 atmospheres, i. ,e. from about 30 to about lbs/sg. in., and at room temperature. If desired, moderately elevated pressures can'fof course, be employed, e. g. from about 250 to 300 lbs/sq, in. The results which we have obtained with our 'novel, process using such conditions of temperatures and pressure have been excellent. The reduction proceeds as rapidly as in any of the procedures of the prior art, and the nitrogen-substituted piperidinol compound, is obtained in excellent yield and in a, high degree of purity.

We have found it possible to eliminate the isolation of the relatively unstable nitrogen-substituted piperidone free base prior to its, dissolution in the solvent in which it Will be hydrogenated. This is advantageous, for the prior art shows that these piperidone compounds are unstable and frequently undergo appreciable decomposition during the process of isolation," nomatter what rnanner ofisolation or what technique is employed. For the production of such nitrogen-substituted:piperidinols, the sodium, enolate salt of the corresponding nitrogemsnbstituted: 3 carbaIkoxy-4-piperidone willusually be available. The. de ired ni o bstit d. p t d ns com qut ii obta ns- 1. b s ar ox t p o he en le a o h ar a k.oxy-4rp p r do e c a y, o xample, refluxing the enolat e salt with hydrochloric acid for a period of from about one to about four hours. The solution ,formed, is; then concentrated to a syrupy mass vacuo on aisteain bath. This syrupy residue then dissolvedin a small q y of Water nd the pi er done tree. base is then liberated from the salt it has formed with the acid by the addition of an alkali such as potassium carbonate or sodium carbonate. The free case may then be extracted from the aqueous mixture by means of any suitable solvent, although it is preferred to use the solvent in which the hydrogenation of the free base will be conducted. We have found that the most convenient and therefore, the preferred process for extracting the free base from the aqueous mixture is to add slowly solid potassium or sodium carbonate to the concentrated aqueous mixture containing the acid salt of the piperidone compound, being certain that sufiicient carbonate is employed to convert all of the acid salt of the piperidone to the free base. This addition of the carbonate is accompanied by rapid agitation and the acid salt of the piperidone reacts almost immediately with the carbonate in the aqueous mixture and liberates the piperidone free base usually in the form of a water immiscible oil. The free base is then extracted from the aqueous mixture with several portions of the solvent in which it is to be hydrogenated. A very convenient manner in which to accomplish this is to slowly add the acid salt of the nitrogen-substituted piperidone compound to an aqueous solution of either sodium or potassium bicarbonate containing sufficient bicarbonate to convert all of the piperidone salt to the free base, which solution is overlaid with the desired amount of solvent to be used in extracting out the free base. The piperidone salt is added to this mixture as the mixture is rapidly stirred. Thus, the acid salt reacts almost immediately with the bicarbonate in the aqueous solution to liberate the free base. Immediately subsequent thereto the free base is extracted from the aqueous solution by the hydrocarbon solvent. In this manner, the solvent solution of the relatively unstable piperidone compound is obtained without the necessity of isolating the free base. To insure complete recovery of the free piperidone base the aqueous solution may be further extracted with a few small portions of hydrocarbon solvents, which extracts are then combined with the original solvent solution. The solvent extracts containing the free base, are then combined and dried over a drying agent such as sodium sulfate. The free base is present in a relatively pure form in the combined solvent extracts ready to be reduced to the piperidinol compound.

These solvent extracts of the piperidone free base are then admixed with the desired amount of Raney nickel catalyst. In the preferred process of our invention we employ a dispersion of the catalyst in the same solvent in which the hydrogenation is to be carried out, i. e. a dispersion of the catalyst in toluene. The Raney catalyst is employed in a large quantity as compared to the amounts in which the catalyst is employed in prior art procedures. However, the overall cost of the catalyst employed in our process is no more than it is in procedures Where only a relatively small amount of Raney nickel catalyst is employed since in our process the catalyst can readily be recovered and reused numerous times without any substantial diminution in its activity. We employ at least about one part of catalyst for each four parts of piperidone free base to be hydrogenated, and we prefer to use at least from about one to about two parts of catalyst for each two parts of free base. If desired, an amount of catalyst which is greater than the Weight of the free base can be employed.

The hydrogenation is then readily accomplished at room temperature by agitating the mixture in an atmosphere of hydrogen at about 2 to 5 atmospheres pressure and allowing the reaction to proceed until adsorption of hydrogen has ceased. The piperidinol compound is then readily separated from the reaction mixture in a pure state by first filtering off the catalyst from the reaction mixture and then evaporating the filtrate in vacuo. The residue that remains after the evaporation is the pure nitrogen-substituted piperidinol compound.

For a fuller understanding of the nature and objects of the invention, reference may be had to the following examples which are given merely as further illustrations of the invention and are not to be construed in a limiting sense.

Example I The hydrochloride salt of N-cyclohexyl-4-piperidone was formed by decarboxylating 15 grams of the sodium enolate salt of N-cyclohexyl-3-carbomethoxy-4-piperidone by refluxing the latter compound for one and one half hours with 75 cc. of 20% hydrochloric acid. The reaction mixture was then concentrated to a syrup in vacuo on a steam bath, and the concentrated mixture was taken up in 50 cc. of water and treated with potassium carbonate to liberate the free base from the hydrochloride salt. The free base separated as an oil. The free base was recovered from the reaction mixture by extracting the reaction mixture with four 50 cc. portions. of toluene. The toluene extracts were combined, dried over sodium sulfate and filtered. Then of the filtered solution was agitated in the presence of hydrogen and in the presence of about 10 grams of Raney nickel catalyst to reduce the piperidone to the corresponding piperidinol. The hydrogenation was carried out at room temperature and under a pressure of about 4 atmospheres. After adsorption of hydrogen had ceased, signifying the completion of reduction, the catalyst was filtered from the solution and the colorless filtrate evaporated in vacuo. The residue which remained was 7.0 grams of colorless crystalline N-cyclohexyl-4-piperidinol which melted at 66-67 C. This yield represented 83.3% of theory based on the assumption that a pure sodium enolate salt of N-cyclohexyl-3-carbomethoxy-4-piperidone was employed for the production of the N-cyclohexyl-4-piperidone and assuming a yield of the latter from the former.

Example II The sodium enolate salt of N-benzyl-3-carbomethoxy- 4-piperidone in a quantity of 22.5 grams (0.08 mole) was admixed with 75 cc. of 20% hydrochloric acid and the mixture refluxed for two hours. The resulting solution contained the hydrochloride salt of N-benzyl-4-piperidone. This solution was then decolorized with activated carbon, filtered and concentrated to a syrup on a steam bath to remove the excess hydrochloric acid. The syrup was redissolved in water and the free N-benzyl-4-piperidone was then liberated from the aqueous solution of the hydrochloride salt thereof by the addition of potassium carbonate to the aqueous solution. The aqueous solution was then extracted with toluene several times, and the combined toluene extracts were then dried using sodium sulfate. When this had been done, the solution was refiltered and then it was agitated at room temperature in the presence of hydrogen under a pressure of 2 to 5 atmospheres in the presence of about 9 grams of Raney nickel catalyst. The rate of reduction was rapid and when the completion of reduction was signified by the cessation of adsorption of hydrogen, the solution was filtered to remove the catalyst and the solvent Was then evaporated in vacuo. The residue was the desired N- benzyl-4-piperidinol. It was a colorless viscous liquid distilling at 127-128 C. at 2 mm. pressure. It was obtained in a yield of 10.3 grams or 67.5% of theory assuming 100% purity of the sodium enolate salt of the N-benzyl-3-carbornethoxy-4-piperidone and assuming 100% conversion of that compound to N-benzy1-4-piperidone.

Example III In the present example, 0.2 mol of the sodium enolate salt of N-methyl-3-carbomethoxy-4-piperidone was decarboxylated by refluxing it with cc. of 20% hydrochloric acid for 3 hours after which the mixture was concentrated to a syrup in vacuo on a steam bath. The syrupy residue was then treated with aqueous sodium hydroxide solution with cooling :iintil str'ongly alkaline and the liberated piperidone extracted. from the alkaline was removed by-tfiltrati'on and the solvent then removed prior art procedures 01; hydrogenating the nitrogensubstituted piperidones to the corresponding nitrogensubstituted; piperidi'nols, since in our process only relatively low hydrogen: pressures are required as compared.

to; the; hydrogen: pressures required in the-prior art hydrogenation procedures. Thus, hydrogen pressures of from about 2 to about atmospheres, i. e. about 30 to--about 75 lbs/sq. in., will, aceomplishthe desired hydrogenation when it is carried, out in accordance with our procedure. Also our procedure is readily carried out at room temperature whereas the prior art procedures require relatively high reaction temperatures.

This application is a continuation-in-part of our copending application Serial No. 118,711 filed September 29, 1949, now Patent No. 2,685,583.

Having described our invention, what we claim as new and desire to secure by Letters Patent is:

1. A process for the hydrogenation of a nitrogen-substituted piperidone compound, the substituted group of which is selected from the class consisting of alkyl, cycloalkyl, aralkyl, and aryl, to the corresponding piperidinol compound which comprises dissolving the piperidone in a hydrocarbon solvent selected from the group consisting of aromatic hydrocarbon solvents and saturated aliphatic hydrocarbon solvents and hydrogenating the said nitrogen-substituted piperidone in the presence of at least about one part of Raney nickel catalyst for each four parts of the piperidone, said hydrogenation being efiYected at about room temperature and under a hydrogen pressure of from about 2 to about atmospheres.

2. A process for the hydrogenation of N-cycloheXyl-4- piperidone to N-cyclohexyl-4-piperidinol which comprises dissolving the N-cycloheXyl-4-piperidone in toluene and hydrogenating the piperidone in the toluene in the presence of at least about one part of Raney nickel catalyst for each four parts of the piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

3. A process for the hydrogenation of N-cyclohexyl-4- piperidone to N-cyclohexyl-4-piperidinol which comprises dissolving the N-cyclohexyl-4-piperidone in naphtha and hydrogenating the piperidone in the naphtha in the presence of at least about one part of Raney nickel catalyst for each four parts of the piperidone, said hydrogenation being eflected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

4. The process of claim 1 wherein at least about one part of Raney nickel catalyst is employed for each two parts of piperidone and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres.

5. The process of claim 2 wherein at least about one part of Raney nickel catalyst is employed for each two parts of piperidone and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres.

6. The process of claim 3 wherein at least about one arrot Raney ni kel catalystis. employed for, each two parts of piperidone and wherein the hydrogenation is carried. out ataboutroom temperature and at a hydrogen pressureof from .aboutZ. to about 5. atmospheres.

7. A process for .the:hydrogenation.of- N-benzylA-piperidone to..Nebenzylt-piperidinol which comprises. dissolving the, N.-benzyl -4-piperidone .in toluene and hydrogenating the piperidone in. the toluene in the presence of at least one part of Raney nickel catalyst for each four parts of piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to.about 20atmospheres.

8. A process for the hydrogenation of N-benzyl-4- piperidone to N-benzyl-4-piperidinol which comprises dissolving the N-benzyl-4-piperidone in naphtha and hydrogenatng the piperidone in: the naphtha in the presence of at leastabout one part of- Raney nickel catalyst for each four parts of piperidone, said hydrogenation being offected at about room temperature and under a hydrogen pressure of from about2 to about 20 atmospheres.

9. The process of claim 7 wherein at least about one part of Raney nickel catalyst is employed for each two parts of piperidone and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure-of fromaboutlto about 55 atmospheres.

10. The processotclaim 8-w.herein at least about one part of Raney nickel catalyst is employed for each two parts: of piperidone-and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres.

11. A process for the hydrogenation of N-metyl-4- piperidone to N-methyl-4-piperidinol which comprises dissolving the N-methyl-4-piperidone in the toluene and hydrogenating the piperidone in the toluene in the presence of at least about one part of Raney nickel catalyst for each four parts of piperidone, said hydrogenation being elfected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

12. The process of claim 11 wherein at least about one part of Raney nickel catalyst is present for each two parts of piperidone and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres.

13. A process for producing a nitrogen-substituted piperidinol compound, the substituted group of which is selected from the class consisting of alkyl, cycloalkyl, aralkyl, and aryl, which comprises admixing a salt formed from a nitrogen-substituted piperidone and an acid with a mixture of an aqueoues solution of at least a stoichiometrically equivalent weight of an alkali metal carbonate and a hydrocarbon solvent selected from the class consisting of aromatic hydrocarbon solvents and saturated aliphatic hydrocarbon solvents, completely dissolving the salt of the piperidone in the mixture thus liberating the free piperidone from the salt and dissolving it in the hydrocarbon solvent, separating the hydrocarbon solvent and the free piperidone which has become dissolved therein from the mixture, and then hydrogenating the piperidone in the solvent in the presence of at least about one part of Raney nickel catalyst for each four parts of piperidone, said hydrogenation being effected at about room temperature and under a hydrogen pressure of from about 2 to about 20 atmospheres.

14. The process of claim 13 wherein N-cyclohexyl-4- piperidone is hydrogenated, the solvent employed is toluene, and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres in the presence of at least about one part of Raney nickel catalyst for each two parts of piperidone compound.

15. The process of claim 13 wherein N-cyclohexyl-4- piperidone is hydrogenated, the solvent employed is naphtha, and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres in the presence of at least about one part of Raney nickel catalyst for each two parts of piperidone compound.

' about 2 to about 5 atmospheres in the presence of at least about one part of Raney nickel catalyst for each two parts of piperidone compound.

17. The process of claim 13 wherein N-benzyl-4-pipcridone is hydrogenated, the solvent employed is naphtha, and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres in the presence of at least about one part of Raney nickel catalyst for each two parts of piperidone compound.

18. The process of claim 13 wherein N-methyl-4-piperidone is hydrogenated, the solvent employed is toluene, and wherein the hydrogenation is carried out at about room temperature and at a hydrogen pressure of from about 2 to about 5 atmospheres in the presence of at least about one part of Raney nickel catalyst for each two parts of piperidone compound.

References Cited in the file of this patent UNITED STATES PATENTS 1,695,666 Schermacher et al Dec. 18, 1928 8 1,980,638 Scheuing et a1. Nov. 13, 1934 2,018,680 Lazier Oct. 29, 1935 2,477,842 Wenner Aug. 2, 1949 FOREIGN PATENTS 485,139 Great Britain Oct. 31, 1929 520,201 Great Britain Apr. 17, 1940 Craig et al.: I. Am. Chem. Soc., vol. 71 (1949), pp. 465-7, 904.

Ugryumov Comp. Rend. Acad. Sci. (USSR), vol. 29

20 (1940), p 48552; Chem. Abst., vol. 35 (1941), p. 3644.

Dankovaetau: J. Gen. Chem. (USSR), vol. 11 (1941), pp. 934-38; Chem. Abst., vol. 37 (1943), p. 381.

Chem. Abst., vol. 24, p. 1863.

Chem. Abst., vol. 40, pp. 5736-7 (1946).

Chem. Abst., vol. 43, p. 4275 (1949). 

1. A PROCESS FOR THE HYDROGENATION OF A NITROGEN-SUBSTITUTED PIPERRIDONE COMPOUND, THE SUBSTITUTED GROUP OF WHICH IS SELECTED FROM THE CLASS CONSISTING OF ALKYL, CYCLOALKYL, ARALKYL, AND ARYL, TO THE CORRESPONDING PIPERIDINOL COMPOUND WHICH COMPRISES DISSOLVING THE PIPERIDONE IN A HYDROCARBON SOLVENT SELECTED FROM THE GROUP CONSISTING OF AROMATIC HYDROCARBON SOLVENTS AND SATURATED ALIPHATIC HYDROCARBON SOLVENTS AND HYDROGENATING THE SAID NITROGEN-SUBSTITUTED PIPERIDONE IN THE PRESENCE OF AT LEAST ABOUT ONE PART OF RANEY NICKEL CATALYST FOR EACH FOUR PARTS OF THE PIPERIDONE, SAID HYDROGENATION BEING EFFECTED AT ABOUT ROOM TEMPERATURE AND UNDER A HYDROGEN PRESSURE OF FROM ABOUT 2 TO ABOUT 20 ATMOSPHERES. 